title: SMG-1 suppresses CDK2 and tumor growth by regulating both the p53 and Cdc25A signaling pathways.
abstract: The DNA damage response is coordinated by phosphatidylinositol 3-kinase-related kinases, ATM, ATR, and DNA-PK. SMG-1 is the least studied stress-responsive member of this family. Here, we show that SMG-1 regulates the G 1/S checkpoint through both a p53-dependent, and a p53-independent pathway. We identify Cdc25A as a new SMG-1 substrate, and show that cells depleted of SMG-1 exhibit prolonged Cdc25A stability, failing to inactivate CDK2 in response to radiation. Given an increased tumor growth following depletion of SMG-1, our data demonstrate a novel role for SMG-1 in regulating Cdc25A and suppressing oncogenic CDK2 driven proliferation, confirming SMG-1 as a tumor suppressor.
authors.affiliation: Department of Molecular Biosciences; The Wenner-Gren Institute; Stockholm University; Stockholm, Sweden; Science for Life Laboratory; Division of Translational Medicine and Chemical Biology; Department of Medical Biochemistry and Biophysics; Karolinska Institute; Stockholm, Sweden.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Gubanova
authors.affiliation: Department of Surgery, Otolaryngology; Yale University; New Haven, CT USA; Cancer Center; Yale University, New Haven, CT USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Issaeva
authors.affiliation: Science for Life Laboratory; Division of Translational Medicine and Chemical Biology; Department of Medical Biochemistry and Biophysics; Karolinska Institute; Stockholm, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Gokturk
authors.affiliation: Department of Molecular Biosciences; The Wenner-Gren Institute; Stockholm University; Stockholm, Sweden.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Djureinovic
authors.affiliation: Science for Life Laboratory; Division of Translational Medicine and Chemical Biology; Department of Medical Biochemistry and Biophysics; Karolinska Institute; Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051357:Cyclin-Dependent Kinase 2; D019869:Phosphatidylinositol 3-Kinases; D010770:Phosphotransferases; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D020687:cdc25 Phosphatases; C514704:SMG1 protein, human; C495894:CDK2 protein, human; C517004:CDC25A protein, human
keywords: CDK2; Cdc25A; G1/S checkpoint; SMG-1; cell cycle; p53; tumor suppressor; tumorigenesis